Vaccine developers still isolate, inactivate, and primarily inject disease-causing microorganisms into arms and legs to prime the peripheral, or systemic, immune system to eradicate them. The problem is that most pathogens enter the body via the mucous membranes of the nasal passages, stomach, eyes, or other tissues, where they encounter the mucosal, not the peripheral, immune system. Where in this vast, interconnected mucosal network can acquired immunity be generated most efficiently? An obvious choice would be to deliver an oral vaccine to the stomach, but difficulties range from measuring the antigen levels absorbed from the mucosal surfaces to knowing how best to package the antigens to prevent enzymes from immediately slicing and dicing them for digestion. An antigen is a unique protein from a virus or bacterium that, like a distinctive fingerprint, the immune system can learn to recognize, attack, and kill. Another fundamental issue is the site of vaccination must be inductive. That is, in addition to being accessible to circulating, infection-fighting immune cells, the mucosal tissue must have its own workshop, or germinal center, that facilitates selective uptake, processing, and presentation of antigen. If the site isn't inductive, it can't generate an acquired immune response and the vaccine won't work. A third fundamental consideration is that researchers have yet to define all of the inductive sites within the mucosal immune system, raising the possibility that viable alternative routes of vaccination are still just a few discoveries away. In the February 2011 issue of the FASEB Journal, National Institute of Dental and Craniofacial Research (NIDCR) grantees may have just made one of these important discoveries. Mouse studies show that the salivary glands can be induced to serve as an inductive site of mucosal immunity. Until now, scientists knew that immune cells circulated to the salivary glands from other tissues (one of the scientific rationales for salivary diagnostics), but surprisingly no group had tested their inductive capability. The scientists directly injected live cytomegalovirus into submandibular salivary glands of several mice and thereafter detected the formation of ectopic follicles. Subsequent analyses showed that these follicles functioned as impromptu germinal centers, allowing antigen-presenting follicular dendritic cells to interact with B and T cells and set in motion the maturation and proliferation of white blood cells. Importantly, the scientists found that the immune response ultimately stopped the spread of the infection to other tissues. The authors noted that their findings suggested that there may be 2 distinct types of inductive sites within the mucosal immune system. The first is a "natural" inductive site, such as those found in the gut or nasal passage. These sites come equipped naturally with M cells (antigen-transporting immune cells), large populations of white blood cells, and distinct germinal centers. The second are "induced" inductive sites, such as those arising in the salivary and mammary glands. An induced site must be inoculated to generate new localized tissue, or follicles, and the needed responses of acquired immunity. According to the authors, "The results reported in these studies support the concept that deliberate salivary gland immunization can serve as an alternative mucosal route for administering vaccines." More research, however, will be needed to establish how this alternative route can best be exploited.